The present invention relates to methods of treating cancers by administering stable platinum-containing formulations by inhalation into a subject""s respiratory tract. More particularly, the present invention relates to methods of administration of cisplatin compounds by inhalation to treat lung cancers.
Cisplatin has been used for the treatment of cancers since the 1970""s. It is an antineoplastic, inhibiting cell division. Cisplatin has been particularly useful in treating testicular and ovarian cancers, with good results also shown for cancers of the head and neck, esophagus, bladder, and lung. Cisplatin converts to an ineffective form in aqueous solution, consequently, cisplatin solutions must be stabilized or the drug will lose its anti-tumor effectiveness. Cisplatin is associated with several adverse side effects, including nausea and vomiting, kidney damage, and hearing loss. Previously cisplatin could only be administered by injection or infusion into a vein. The present invention, however, allows for the production and use of stable cisplatin powders, sprays, and aerosol solutions, dispersions, or liposome or liposome associated liquids, that can be administered by inhalation.
In comparison to injection or infusion, the administration of a drug by inhalation is attractive. For some cancers, inhalation can provide a more localized administration of the therapeutic agent and, therefore, can be more effective. The increased effectiveness of local administration will be seen most in the lungs and bronchial pathways, but as the platinum-containing drug is cleared from the lungs via cellular uptake and transfer to the lymphatic system, it can act on cancers affecting other areas, such as the liver, spleen, and bone marrow. With this local application approach, inhalation can reduce the side effects of cisplatin and other platinum-containing agents normally encountered after intravenous administration, due to limited bioavailability to tissues and organs via the blood stream. It can also be easier to administer therapeutics by inhalation. Cisplatin when administered intravenously is rapidly bound to various proteins found in the blood plasma, thus inactivating most of the intact platinum compound. In vivo studies indicate that this inactivation will not occur in the lung since the dose required to elicit a response in animal models is 10-100 fold more effective. Thus, the dose which is administered by inhalation can be 10-100 fold lower than the dose administered intravenously. Therefore the therapeutic index can be improved significantly. When appropriate medically, the drug can be self-administered, leading to better patient compliance and reduced cost.
Administration of therapeutic agents by inhalation does have drawbacks, however. Due to the immune response of the lung and natural breathing parameters designed to expel foreign particles, drugs that are administered by inhalation quickly clear the lung and, therefore, often yield short-term therapeutic effects since they become subject to chemical and enzymatic in-vivo degradation and/or expulsion via the airways.
The present invention can overcome the difficulties and disadvantages in current inhalation therapy and offer new advantages that can benefit the treatment of cancers by local administration. These methods minimize systemic exposure of non-cancerous cells in the body to the toxic effects of the platinum-containing drug. Less of a dose can be administered, since it is applied for local activity and is targeted to specific diseased cells in the lung rather than distributed throughout the body. The result can be an improved therapeutic index. In addition, formulations of the present invention can be prepared that will be absorbed systemically following inhalation. Such systemic absorption can occur with less toxicity. Furthermore, for some formulations, the release of the platinum can occur over a prolonged period of time.
The present invention describes novel methods of treating cancers involving inhalation of stable platinum-containing formulations. The various platinum-containing formulations are comprised of a platinum-based drug, such as cisplatin, and any stabilizers, phospholipids or liposomes, including liposomes between about 10 nm and about 1000 nm, preferably 15-300 nm, more preferably 25-100 nm, or those greater than 1 micron in diameter, preferably 2-5 microns in diameter, or polymers needed for maximum effectiveness. Additionally, when desired, the platinum-containing formulation can contain transferrin or a platinum-transferrin complex, and use carriers, such as hydrofluorocarbons or fluorochlorocarbons (including 1,1,1,2,3,3,3-heptafluoropropane, 1,1,1,2-tetrafluoroethane, dichlorodifluoromethane, trichlorofluoromethane, or 1,2-dichloro-1,1,2,2-tetrafluoroethane), and/or excipients, such as sugars, including milk sugars such as lactose.
In addition or alternatively to cisplatin, other platinum-containing drugs that may be used in the formulation include one or more of: carboplatin, oxaliplatin, iproplatin, tetraplatin, transplatin, JM118 (cis-amminedichloro(cyclohexylamine)platinum(II)), JM149 (cis-amminedichloro(cyclohexylamine)-trans-dihydroxoplatinum(IV)), JM216 (bis-acetato-cis-amminedichloro(cyclohexylamine)platinum(IV)) and JM335 (trans-amminedichloro(cyclohexylamine)dihydroxoplatinum(IV)).
A stable platinum-based formulation can be produced by milling a platinum-based drug, such as cisplatin, to a powder and combining it with sodium chloride as a dry powder blend suitable for administration by inhalation. The resulting formulation can include one or more phospholipids or liposomes. The presence of extraneous chloride ions are known to prevent the cisplatin from degrading by loss of the chloridexe2x80x94constituents of the cisplatin molecule when the drug is dissolved in water. The extra chloride will protect the molecule from degrading as rapidly in the presence of the moisture in the lung. The added presence of lipids or liposomes can protect against hydration, permitting adherence to the lung surface, and provide sustained contact which can allow for longer release periods.
Alternatively, the platinum-containing drug can be combined with a sodium chloride solution, then the water removed from the solution by such methods as evaporation, freeze drying or spray drying, to form sodium chloridexe2x80x94platinum-containing drug combination, including, but not limited to, sodium chloride crystals which protect the platinum containingxe2x80x94drug from degradation. These crystals can then be precipitated in such a way that they are appropriate for administration by inhalation or milled to a powder suitable for administration by inhalation.
A stable platinum-based formulation can be produced by combining cisplatin with transferrin to form a cisplatin-transferrin complex, then adding a phospholipid to produce a compound suitable for inhalation. This formulation can be combined with appropriate additives to enable it to be inhaled as a dry power, a solution, a dispersion, or a suspension.
The various platinum-containing formulations of the present invention can be administered to the subject in the form of a powder. The powder may contain one or more lipids such as phospholipids and/or excipients. The powder may be delivered to the subject""s respiratory tract as an aerosol which may contain one or more sugars used as excipients. The powder may also be administered to the subject by a nebulizer.
The various platinum-containing formulations of the present invention can also be administered to the subject""s respiratory tract in the form of a liquid, including liquids that contain up to about 50% ethanol, preferably about 10%, more preferably about 2-3% most preferably about 2% by weight. The liquid may be delivered to the subject as an aerosol, a nebulized spray or other sprayed composition.
In particular, the present invention describes methods of treating lung cancers by inhalation of platinum-containing formulations into the subject""s respiratory tract. Lung cancers include both small cell and non-small cell primary lung cancer as well as cancers that metastasize to the lungs or the lung lymphatics. In addition, the invention describes methods of treating other cancers, such as bronchoalveolar carcinoma, leukemia, myelomas, mesotheliomas, cancers of the bronchial pathways, trachea, or esophagus, and cancers of the liver or spleen, by inhalation of a platinum-containing formulation which will be cleared from the lungs via cellular uptake and transferred to the lymphatic system.
xe2x80x9cAntineoplastic agentxe2x80x9d is an agent that prevents the development, growth or proliferation of malignant cells.
xe2x80x9cCancerxe2x80x9d is the uncontrolled growth of abnormal cells.
xe2x80x9cStable platinum-containing formulationxe2x80x9d is a formulation containing a platinum-containing compound or ion wherein the compound or ion is stable for transformation for a time sufficient to be therapeutically useful.
xe2x80x9cStabilizerxe2x80x9d is an agent that prevents or slows the transformation or deactivation of a platinum-containing compound or ion in a platinum-containing formulation.
xe2x80x9cSubjectxe2x80x9d or xe2x80x9cindividualxe2x80x9d is a human or animal in need of treatment for cancer.
Table 1 is a tabular description of formulations for cisplatin-containing compositions to be used in the present invention.